Co-Regulation of Alternative Lengthening of Telomeres and Chromatin Dynamics in ATRX-DAXX deficient cancer cells

ATRX-DAXX 缺陷癌细胞中端粒选择性延长和染色质动态的共同调节

基本信息

批准号：
10652320
负责人：
Roderick O'Sullivan
金额：
$ 44.78万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-06-23 至 2027-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10652320
关键词：
ADP ribosylation ATRX gene Acute Adopted Affect Automobile Driving Bypass Cell Cycle Cell division Cells Cessation of life Chromatin Chromatin Modeling Chromatin Remodeling Factor Chromosomes Compensation Complex DAXX gene DNA Damage DNA Sequence Alteration Data Dedications Deposition Detection Development Disease Disseminated Malignant Neoplasm Enhancers Ensure Epigenetic Process Event Exhibits G2 Phase Genes Genetic Genetic Transcription Genomic approach Glioma Histone H3.3 Maintenance Malignant Neoplasms Mediating Mediator Metabolic Microscopy Missense Mutation Modeling Molecular Mutation Names Nucleosomes Patients Prognosis Property Proteins Proteomics Recurrence Regulation Reporting Role Running Signal Transduction Stress Structure Telomere Maintenance Telomere Pathway cancer cell chromatin remodeling cytotoxicity epigenome epithelial to mesenchymal transition gain of function genome integrity genomic locus histone modification improved innovation loss of function mutation prevent promoter public health relevance reconstitution recruit repaired response targeted cancer therapy telomere therapeutic target trait tumor tumorigenesis ultra high resolution

项目摘要

Abstract Cancer cells must activate a telomere elongation mechanism and acquire genomic alterations. Many of the most lethal cancers rely on the Alternative Lengthening of Telomeres (ALT) pathway. ALT is a specialized homology directed repair (HDR) mechanism dedicated to repair and elongate telomeres, thereby ensuring the proliferative immortality of these cancer cells. Recurrent inactivating missense mutations in genes encoding the ATRX-DAXX chromatin remodeling/histone H3.3 deposition complex exhibit a strong concordance with tumors in which ALT is activated, with both arising late in metastatic disease. These loss of function mutations disrupt ATRX-DAXX mediated assembly of chromatin, provoking replicative stress and double-strand breaks (DSBs) within telomeres that is believed to stimulate ALT-associated HDR. Whereas the HDR mechanisms that underpin ALT have been extensively studied, the mechanisms governing how cells compensate for loss of ATRX-DAXX to maintain chromatin while also acquiring metastatic traits remain ill-defined. This proposal builds on our recent report that upon inactivation of ATRX-DAXX, a related chromatin assembly factor known as HIRA becomes indispensable for de novo histone H3.3 deposition and telomere extension in ALT cancer cells. Furthermore, we discovered that the depletion of HIRA provoked acute systemic death of ATRX-DAXX deficient cells. Strikingly, this cytotoxicity was reversed by reconstitution of ALT cells with wild type ATRX protein. These data provided compelling evidence for a compensatory function adopted by HIRA due to ATRX-DAXX deficiency that could be harnessed to eliminate ALT cancer cells.

抽象的癌细胞必须激活端粒延长机制并获得基因组改变。许多最致命的癌症依赖于端粒替代延长 (ALT) 途径。 ALT 是一种专门同源定向修复（HDR）机制致力于修复和延长端粒，从而确保这些癌细胞的增殖永生性。编码基因的反复失活错义突变 ATRX-DAXX 染色质重塑/组蛋白 H3.3 沉积复合物表现出强烈的一致性 ALT 被激活的肿瘤，两者均在转移性疾病晚期出现。这些功能丧失突变破坏 ATRX-DAXX 介导的染色质组装，引发复制应激和双链断裂端粒内的 DSB（DSB）被认为可以刺激 ALT 相关的 HDR。而 HDR 机制 ALT 的基础已被广泛研究，控制细胞如何补偿 ALT 损失的机制 ATRX-DAXX 在维持染色质的同时获得转移性状的作用仍不明确。这个提议基于我们最近的报告，ATRX-DAXX 失活后，一种已知的相关染色质组装因子因为 HIRA 对于 ALT 癌症中组蛋白 H3.3 的从头沉积和端粒延伸变得不可或缺细胞。此外，我们发现 HIRA 的消耗会引起 ATRX-DAXX 的急性全身性死亡缺乏细胞。引人注目的是，用野生型 ATRX 重建 ALT 细胞可逆转这种细胞毒性蛋白质。这些数据为 HIRA 由于以下原因而采取的补偿功能提供了令人信服的证据： ATRX-DAXX 缺陷可用于消除 ALT 癌细胞。